Solid dispersion systems for enhanced dissolution of poorly water-soluble candesartan cilexetil: In vitro evaluation and simulated pharmacokinetics studies.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Benzimidazoles*/pharmacokinetics ; Biphenyl Compounds*/chemistry ; Biphenyl Compounds*/pharmacokinetics ; Tetrazoles*/chemistry ; Tetrazoles*/pharmacokinetics ; Angiotensin II Type 1 Receptor Blockers*/chemistry ; Angiotensin II Type 1 Receptor Blockers*/pharmacokinetics; Solubility ; Povidone/chemistry ; Biological Availability ; Drug Stability ; Drug Compounding ; Chromatography, High Pressure Liquid ; In Vitro Techniques

Background: Candesartan cilexetil (CC) is a selective angiotensin II receptor antagonist widely used to treat hypertension. CC is a substrate of P-glycoprotein (P-gp), causing its efflux to the intestinal lumen. It is also practically insoluble in water and has low oral bioavailability (14%). Thus, the current study aims to improve the in vitro dissolution of CC by developing solid dispersion systems (SDSs) and corroborating the in vitro results using a simulated pharmacokinetics study.
Methods: The SDSs were prepared using polyvinyl pyrrolidone (PVP) as a water-soluble polymer, Eudragit E100 (EE100) as a pH-dependent soluble carrier, and a combination of these two polymers. The saturation solubility and the dissolution rate studies of the prepared systems in three dissolution media were performed. The optimized system SE-EE5 was selected for further investigations, including DSC, XRD, FTIR, FESEM, DLS, TSEM, IVIVC convolution study, and stability studies.
Results: The solubility of CC significantly increased by a factor of 27,037.344 when formulated as a solid dispersion matrix using EE100 at a ratio of 1:5 (w/w) drug to polymer (SE-EE5 SD), compared to the solubility of the pure drug. The mechanism of solubility and dissolution rate enhancement of CC by the optimized SDS was found to be via the conversion of the crystalline CC into the amorphous form as well as nanoparticles formation upon dissolution at a pH below 5. The instrumental analysis tests showed good compatibility between CC and EE100 and there was no chemical interaction between the drug and the polymer. Moreover, the stability tests confirmed that the optimized system was stable after three months of storage at 25°C.
Conclusion: The utilization of the solid dispersion technique employing EE 100 polymer as a matrix demonstrates significant success in enhancing the solubility, dissolution, and subsequently, the bioavailability of water-insoluble drugs like CC.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Ali et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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R85M2X0D68 (candesartan cilexetil)
0 (Benzimidazoles)
0 (Biphenyl Compounds)
0 (Tetrazoles)
0 (Angiotensin II Type 1 Receptor Blockers)
FZ989GH94E (Povidone)

Date Created: 20240606 Date Completed: 20250228 Latest Revision: 20250228

20250301

PMC11156308

10.1371/journal.pone.0303900

38843120